Iodo derivatives of steroid compounds and a process of manufacturing the same



Patented Feb. 16, 1943 1on0 DERIVATIVES F s'rEaom 00M- 7 POUNDS AND A PROCESS or MANUFAC- TURINGTHE SAME Burckhardt Helferich and Erich Giinther, Leipzig,

Germany, assignors to Schering Corporation,

Bloomfield, N. J a corporation of New Jersey No Drawing. Application 'October 12, 1938, Serial No. 234,632. In Germany October. 12, 1937 16 Claims. (01. zen-397.2)

This invention relates to new iodo derivatives of steroidcompounds and a process of manufacturing the same.

Iodo compounds of steroids, which are derived from steroid alcohols by replacement of the hydroxyl group by iodine are practically unknown. In the Monatsheften iiir' Chemie, volume 33 (1912), page'447, there is described only the manufacture of cholesteryl bromide from cholesterol with phosphorous tribromide; it is true that in the same paper the author states that by analogous methods also the cholesteryl iodide is obtainable, but neither in. this nor in subsequent papers is there any reference to the substance.

It is further known from Hoppe-Seylers Zeitschrift fiir Physiolog. Chem., volume 213 (1932), page 119, that cholesteryl bromide reacts with sodium iodide in acetone at 110-125 C.; there is thereby produced however not, as one would expect by analogy with reactions of simpler bromides, the cholesteryl iodide, but, obviously with splitting off of halogen hydride, a cholestadiene. It is seen therefrom, as also from many other experimental results in the steroid series, that reactions known per se cannot be applied with safety to these classes of substances, which on account of their particular carbon skeleton and the particular chemical and physical properties due to their constitution, render extensive and tedious experimental and inventive researches necessary even when a process is concerned which is known per se in other classes of substances.

The present process now renders possible in a new way the production of iodine compounds of steroids from the corresponding hydroxv steroids, for example steriod alcohols or steroid enois. According to the invention the hydroxy steroids, for example cholesterol or ergosterol, are first converted into esters of true organic sulphonic acids according to one of the known methods (compare Liebigs Annalen, volume 448, page 128; Hoppe-S'eylers Zeitschrift fiir physiologische Chemie, volume 202, page 232-36 and volume 207, page 147-49, Berichte der deutschen chemischen Gesellschaft, volume 69, page 2776- '78, and volume 70, page 1446-50). The sulphonic acid esters obtained, such as alkyl sulphonic acid esters or aryl sulphonic acid esters, are then treated with iodides, preferably in organic solvents, advantageously in acetone, and at elevated temperature whereby the corresponding steroid iodides and alkyl or aryl sulphonic acid salts are produced.

The reaction corresponds to the followin equation:

in which R. indicates an organic residue such as alkyl or aryl, Me a cation and St a steroid residue. l

The sulphonic acid salt can be employed again in known manner for the production of new esters, for example by way of the sulphonic acid chloride.

Asfsulphonic acid esters there serve for examplev those of aliphatic sulphonic acids such as the methane and ethane sulphonic acid or likewise those of the aromatic series, such as benzene and toluene sulphonic acid esters and the like. a

The reaction temperatures in general lie between and 130 C.; in any case so low that the iodide produced cannot further change to any considerable extent.

The fact that esters of p-toluene sulphonic acid can be caused to react with sodium iodide in acetone to the corresponding iodides is known per se from other branches of organic chemistry; thus, many iodohydrins of the sugar group have been produced in this manner. In the case of the very unstable iodides of the steroid series this has however not been described and no work has hitherto been done with alkyl sulphonic acid esters. n

The'yieldsaccording to the new process are good. 'The iodo compounds obtained are intended to; find application for pharmaceutic use as "therapeutic agents and also as intermediate products.

The following examples illustrate the invention:

Examples (1) 16 grams of cholesterol in cos. of absolute pyridine are mixed ice cold with an ice cold mixture of 5.4 cos. of methane sulphonic acid chloride in 005. of absolute pyridine, the clear solution thereby obtained kept for sixteen hours at low temperature, about 0-10 C. and the methane sulphonic acid ester of cholesterol so produced is separated by taking up with water and ether, washing, drying and evaporating the ether and by recrystallisation from petrol ether. Melting oint -122 C.; =35.7.

5 grams of this methane sulphonyl cholesterol are heated with 10 grams of anhydrous sodium iodide in about 100 cos. of dry acetone for 2 hours to about 60 0., care being taken in the first place that the whole is thoroughly mixed. The

sodium methyl sulphonate crystallises after cooling almost completely and at the same time also the cholesteryl iodide for the major part. By washing of the mixture filtered with suction with water the sulphonate can easily be separated from the water-insoluble cholesteryl iodide. Yield 4 grams of iodide. By recrystallisation from about 20 cos. of acetone it can easily be completely purified. Melting point 104-106 (3.; [a] =13.4= in chloroform; the iodine content and also the ordinary composition correspond to the formula C27H45I.

(2) 5 grams of the p-toluene sulfonic acid ester of cholesterol are heated withgrams of anhydrous sodium iodide in about 70 cos. of acetone for 2-3 hours to about 60 C. in a closed vessel. There crystallises a mixture of sodium p-toluene sulphonate and cholesteryl iodide. After standing for several hours at low temperature the mass is separated and well ground with water. The sodium salt passes into solution, the cholesteryl iodide remains in a yield of 3-4 grams and can be purified as described in Example 1.

(3) From ergosterol and methane sulphonic acid chloride in pyridine the methane sulphonyl ergosterol is produced; the latter begins to become discoloured at about 110 C. and melts with decomposition at about 114 C.; [a] =-73.8 in chloroform.

1 gram of this ester in about 60 cos. of acetone is mixed with a solution of 2 grams of anhydrous sodium iodide in about cos. of acetone and the solution heated for hours to 60-65" C. After cooling, the whole is filtered from the sodium methane sulphonate which has crystallised out, the filtrate evaporated to dryness and the residue extracted with ether. After evaporation of the solvent there remains an ergosteryl iodide in 60% yield as a viscous somewhat coloured syrup. In order to avoid as far as possible decomposition of the very sensitive substance the isolation should be carried out as far as possible in the dark with exclusion of daylight or bright lamp light. The product corresponds to the formula C2sH4sI.

Instead of sulphonic acid esters of alcoholic cholesterol and ergosterol also other suitably constituted sulphonic acid esters of hydroxy compounds of the steroids can find application as starting materials insofar as they contain in the ring system an alcoholic hydroxy group. Similarly suitable are also the corresponding enol derivatives which possess an enolic hydroxyl group or a keto group which can react inthe enol form.

Hence as starting materials are suitable the corresponding derivatives of the androstane and pregnane series compounds or of other sterols, sitosterol, stigmasterol, phytosterol, coprosterol,

cinchol or of cholanic acids and their lower homologues, nor-cholanic or bisnorcholanic acids, of bile acids, saponines, cardiac poisons and their genins and so on.

Of course, the amounts of the various agents and the type and the amounts of the sulphonic acid esters of hydroxy compounds of steroids used in carrying out the invention; the temperatures employed and the other reaction conditions may be varied within the limits obvious to those skilled in the art; hence, many other changes and variations may be made in accordance with the principles set forth herein and in the claims annexed hereto.

What we claim is:

1. Process for the manufacture of iodo derivatives of steroid compounds, wherein the hydroxy compounds of steroids are treated in the form of their organic sulphonic acid esters with iodides soluble in organic solvents.

2. Process as claimed in claim 1, in which the sulphonic acid esters are treated with inorganic iodides soluble in organic solvents.

v} 3. Process as claimed in claim 1, in which the sulphonic acidesters are treated with alkali metal iodides.

4. Process as claimed in 1, in which alkyl sulphonic acid esters are employed as starting materials.

5. Process as claimed in claim 1-, in which methane sulphonic acid esters are employed as starting materials.

6. Process as claimed in claim 1, in which methane sulphonyl cholesterol is employed as starting material.

7. Process as claimed in claim 1, in which methane sulphonyl ergosterol is employed as starting material.

8. Process as claimed in claim' 1, in which aryl sulphonic acid esters are employed as starting material.

9. Process as claimed in claim' 1, in which toluene sulphonic acid esters are employed as starting material.

10. Process as claimed in claim 1, in which p-toluene sulphonic acid cholesterol ester is employed as starting material.

11. Process as claimed in claim 1', in which the sulphonic acidesters are iodised in organic solvents.

12. Process as claimed in claim 1, in which the sulphonic acid esters are iodised in acetone.

13. Process as claimed in claim 1, in which the sulphonic acid esters are iodised at 50-130" C. 14. Ergosteryl iodide of the formula C2BH43I. 15. A-nuclear iodide derivative of a phytosterol. 16. The enol-ic iodide of a steroid ketone.

BURCKHrlRDT HELFERICH. ERICH GUNTHER. 

